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Matrix Metalloproteases in Pancreatic Ductal Adenocarcinoma: Key Drivers of Disease Progression?

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Matrix Metalloproteases in Pancreatic Ductal Adenocarcinoma: Key Drivers of Disease Progression? biology Review Matrix Metalloproteases in Pancreatic Ductal Adenocarcinoma: Key Drivers of Disease Progression? Etienne J. Slapak 1,2,3, JanWillem Duitman 1,2, Cansu Tekin 1,2,3 , Maarten F. Bijlsma 2,3 and C. Arnold Spek 1,2,* 1 Center of Experimental and Molecular Medicine, University of Amsterdam, Amsterdam UMC, 1105 AZ Amsterdam, The Netherlands; [email protected] (E.J.S.); [email protected] (J.D.); [email protected] (C.T.) 2 Laboratory for Experimental Oncology and Radiobiology, Cancer Center Amsterdam, University of Amsterdam, Amsterdam UMC, 1105 AZ Amsterdam, The Netherlands; [email protected] 3 Oncode Institute, 1105 AZ Amsterdam, The Netherlands * Correspondence: [email protected] Received: 26 March 2020; Accepted: 15 April 2020; Published: 18 April 2020 Abstract: Pancreatic cancer is a dismal disorder that is histologically characterized by a dense fibrotic stroma around the tumor cells. As the extracellular matrix comprises the bulk of the stroma, matrix degrading proteases may play an important role in pancreatic cancer. It has been suggested that matrix metalloproteases are key drivers of both tumor growth and metastasis during pancreatic cancer progression. Based upon this notion, changes in matrix metalloprotease expression levels are often considered surrogate markers for pancreatic cancer progression and/or treatment response. Indeed, reduced matrix metalloprotease levels upon treatment (either pharmacological or due to genetic ablation) are considered as proof of the anti-tumorigenic potential of the mediator under study. In the current review, we aim to establish whether matrix metalloproteases indeed drive pancreatic cancer progression and whether decreased matrix metalloprotease levels in experimental settings are therefore indicative of treatment response. After a systematic review of the studies focusing on matrix metalloproteases in pancreatic cancer, we conclude that the available literature is not as convincing as expected and that, although individual matrix metalloproteases may contribute to pancreatic cancer growth and metastasis, this does not support the generalized notion that matrix metalloproteases drive pancreatic ductal adenocarcinoma progression. Keywords: MMP; MMP2; MMP9; MMP7; MMP14; matrix metalloproteases; PDAC; pancreatic cancer 1. Introduction Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with the worst survival outcome of any cancer [1]. Its incidence, which is around 10 per 100,000 individuals, is rising in developed countries [2,3], with 458 thousand new cases and 432 thousand deaths in 2018 worldwide [4]. The 5-year survival rate is around 9%, and the 10-year mortality is approaching 99% [5]. Progress towards improving survival has been slow, and current treatment options are inadequate. The only significant progress that has been made is in the form of lower mortality rates for patients eligible for resections, and a slight prolongation and improved quality of life in patients with inoperable disease with the use of chemotherapeutic agents. Single-agent gemcitabine treatment has been the standard of care for inoperable PDAC for many years, although the observed benefits are small in daily practice [6–9] and seem restricted to patients with a good performance status [10]. More recently, nanoparticle albumin-bound paclitaxel was shown to exert superior antitumor activity compared to gemcitabine monotherapy, thereby establishing nab-paclitaxel and gemcitabine combination therapy Biology 2020, 9, 80; doi:10.3390/biology9040080 www.mdpi.com/journal/biology Biology 2020, 9, 80 2 of 21 as first-line chemotherapy regimens in PDAC [11]. In patients with a good performance status, combination therapy with folinic acid, fluorouracil, irinotecan and oxaliplatin (FOLFIRINOX) is superior over other treatments [12] and FOLFIRINOX is consequently emerging as the new standard of care for relatively fit patients [13]. Importantly however, even in the specific group of patients eligible for FOLFIRINOX treatment, the survival benefit is limited [14]. 1.1. Tumor Microenvironment of PDAC PDAC is characterized by a strong desmoplastic reaction, which results in an archetypal tumor microenvironment, consisting of a dense stroma surrounding the tumor cells [15,16]. The stroma forms the bulk of the tumor, taking up to 90% of the total tumor mass and consists of many cellular and acellular components like (myo)fibroblasts, macrophages, blood vessels and extracellular matrix components such as, among others, collagen I, collagen IV, laminin and fibronectin. In the stroma, the extracellular matrix has traditionally been considered to be a stable structure that mainly plays a supportive role in maintaining tissue morphology. Nowadays, however, it is evident that the extracellular matrix forms a dynamic and versatile milieu that affects the fundamental processes of the surrounding cells [17,18]. Accordingly, the loss of extracellular matrix homeostasis and integrity is considered one of the hallmarks of cancer and typically defines transitional events, resulting in cancer progression and metastasis [19]. Moreover, the loss of extracellular matrix homeostasis due to stromal depletion aggravates pancreatic cancer progression in preclinical animal models [20–22]. 1.2. Matrix Metalloproteases in the Tumor Microenvironment The desmoplastic PDAC stroma contains many different proteases that play a key role in the crosstalk between tumor and stromal cells. An intriguing group of proteases in the tumor microenvironment consist of matrix metalloproteases (MMPs), which are primarily known for their ability to degrade extracellular matrix components. Altered expression and/or activity of MMPs in the tumor microenvironment is likely to lead to the loss of homeostasis of the extracellular matrix, thereby driving PDAC progression. Based upon this notion, MMPs are considered important contributors to PDAC progression and experimental PDAC studies frequently use MMPs as surrogate markers for treatment responses. Decreased MMP levels are, nowadays, considered as important signs of the anti-tumorigenic potential of the gene/compound/miRNA under study. In the current review, we address whether the literature supports the concept that MMPs drive PDAC progression and if decreased MMP levels under experimental settings are indicative of the treatment response. To this end, we performed a systematic review of patient and experimental animal studies, focusing on MMPs in PDAC. 1.3. Overview of Matrix Metalloproteases MMPs are calcium-dependent zinc-containing endopeptidases of the metzincin protease superfamily. They typically contain an N-terminal propeptide of approximately 80–90 amino acids, with a conserved PRCGXPD motif that is responsible for maintaining latency via the binding of the cysteine residue to the zinc atom in the active site [23]. After the proteolytic removal of the propeptide, the active form of MMP contains a calcium-dependent catalytic domain of around 200 amino acids, which contains a hydrophobic S10-pocket that determines substrate specificity, proceeded by a linker region of variable length, and the C-terminal hemopexin-like domain, which spans approximately 200 amino acids. The hemopexin-like domain, which is absent in some MMP family members, plays a functional role in substrate binding and/or in interactions with tissue inhibitors of metalloproteases (TIMPs), a family of specific MMP protein inhibitors [24]. Since the identification of a diffusible collagenolytic factor in living amphibian tissue that is capable of degrading undenatured calf skin collagen [25], a total of 24 MMPs have been identified in humans [26]. According to their substrate specificity, MMPs are classified into subfamilies: (1) collagenases, (2) gelatinases, (3) stromelysins, (4) matrilysins, (5) membrane-type MMPs and Biology 2020, 9, 80 3 of 21 (6) others. Despite the general acceptance of the classification system based on extracellular matrix substrates, MMPs are rather promiscuous in substrate recognition and also proteolytically cleave substrates beyond extracellular matrix proteins. 2. Methods To provide a comprehensive overview of the role of MMPs in PDAC, a systematic PubMed search without restrictions was performed. A combination of the search terms “pancreatic cancer” and every individual MMP (both using the official gene name and the common name; see Supplementary Materials Table S1) was used to retrieve papers published up to 1 March 2020. All papers were independently screened by their title and abstract, followed by full text assessment to include papers that contained MMP expression analysis in PDAC patients and papers that contained animal experiments that targeted (either genetically or pharmacologically) MMPs in pancreatic cancer models. The excluded papers were those that contained in vitro data only, papers that assayed MMP levels in experimental animal models without interventions or genetic modifications, or papers that did not focus on PDAC. 3. Results We retrieved 64 papers focusing on collagenases, 642 papers focusing on gelatinases, 51 papers focusing on stromelysins, 93 papers focusing on matrilysins, 66 papers focusing on transmembrane MMPs and 21 papers focusing on other MMPs (Figure1). After the removal of duplicates, 816 eligible studies were identified and were vigorously screened to obtain those that contained patient data and/or animal experiments in which MMPs were targeted. This resulted in the inclusion of 14 papers focusing on collagenases, 60 on gelatinases,
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